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[Background] Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC)., [Objective] To report on 2-yr disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and circulating tumor DNA (ctDNA) in the ABACUS trial., [Design, setting, and participants] ABACUS was a multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy., [Intervention] Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected., [Outcome measurements and statistical analysis] The primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers were published previously. Secondary outcomes were 2-yr DFS and OS. A biomarker analysis correlated with relapse-free survival (RFS) was performed, which includes FOXP3, major histocompatibility complex class I, CD8/CD39, and sequential ctDNA measurements., [Results and limitations] The median follow-up time was 25 mo (95% confidence interval [CI] 25–26). Ninety-five patients received at least one cycle of atezolizumab. Eight patients did not undergo cystectomy (only one due to disease progression). The pCR rate was 31% (27/88; 95% CI 21–41). Two-year DFS and OS were 68% (95% CI 58–76) and 77% (95% CI 68–85), respectively. Two-year DFS in patients achieving a pCR was 85% (95% CI 65–94). Baseline PD-L1 and tumor mutational burden did not correlate with RFS (hazard ratio [HR] 0.60 [95% CI 0.24–1.5], p = 0.26, and 0.72 [95% CI 0.31–1.7], p = 0.46, respectively). RFS correlated with high baseline stromal CD8+ (HR 0.25 [95% CI 0.09–0.68], p = 0.007) and high post-treatment fibroblast activation protein (HR 4.1 [95% CI 1.3–13], p = 0.01). Circulating tumor DNA positivity values at baseline, after neoadjuvant therapy, and after surgery were 63% (25/40), 47% (14/30), and 14% (five/36), respectively. The ctDNA status was highly prognostic at all time points. No relapses were observed in ctDNA-negative patients at baseline and after neoadjuvant therapy. The lack of randomization and exploratory nature of the biomarker analysis are limitations of this work., [Conclusions] Neoadjuvant atezolizumab in MIBC is associated with clinical responses and high DFS. CD8+ expression and serial ctDNA levels correlated with outcomes, and may contribute to personalized therapy in the future, [Patient summary] We showed that bladder cancer patients receiving immunotherapy followed by cystectomy have good long-term outcomes. Furthermore, we found that certain biological features can predict patients who might have particular benefit from this therapy., Bernadett Szabados—research funding from MSD and Roche; honoraria from Roche, MSD, and BMS. Mark Kockx—employee of CellCarta. Zoe June Assaf—employee of Roche. Pieter-Jan van Dam—employee of CellCarta. Alejo Rodriguez-Vida—research funding and honoraria from Roche, BMS, and Pfizer; research funding from Novartis and Astellas. Ignacio Duran—research funding and honoraria from Roche, BMS, Pfizer, and Johnson & Johnson; research funding from Astellas. Simon J. Crabb—research funding and honoraria from Roche, MSD, Pfizer, Exelixis, and Clovis. Michiel S. Van Der Heijden—research funding and honoraria from BMS, AstraZeneca, MSD, Novartis, Pfizer, MSD, and Seattle Genetics. Albert Font Pous—research funding and honoraria from MSD, Pfizer, and Astellas. Gwenaelle Gravis—research funding and honoraria from Roche, AstraZeneca, Pfizer, and Astellas. Urbano Anido Herranz—research funding and honoraria from Roche, MSD, Exelixis, and Astellas. Andrew Prothoroe—research funding and honoraria from Astellas, Pfizer, Novartis, and BMS. Alain Ravaud—research funding and honoraria from MSD, Roche, BMS, and Pfizer. Denis Maillet—research funding and honoraria from MSD and Roche. Maria Jose Mendez—research funding and honoraria from Roche and Pfizer. Cristina Suarez—research funding and honoraria from Pfizer, BMS, Roche, AstraZeneca, and Astellas. Mark Linch—research funding and honoraria from BMS, Roche, Pfizer, Astellas, and AstraZeneca. Aaron Prendergast and Charlotte Tyson—no conflicts. Diana Stanoeva, Sofie Daelemans, and Miche Rombouts— employee of CellCarta. Sanjeev Mariathasan—employee of Genentech. Joy S. Tea—employee of Roche. Kelly Mousa—no conflicts. Romain Banchereau—employee of Genentech. Daniel Castellano—research funding and honoraria from Astellas, BMS, Roche, and AstraZeneca. Thomas Powles—honoraria from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; research funding from AstraZeneca, BMS, Exelixis, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; travel/accommodation/expenses from Roche, Pfizer, MSD, AstraZeneca, and Ipsen.

Introduction Cabazitaxel multiple rechallenges may be a treatment option in heavily pretreated patients with metastatic castration‐resistant prostate cancer (mCRPC) who had a good initial response to cabazitaxel and who are still fit to receive it. Our objective was to assess the efficacy and toxicity of multiple rechallenges. Patients and methods We retrospectively identified 22 mCRPC patients previously treated with docetaxel and/or androgen receptor‐targeted agents who received multiple cabazitaxel rechallenges in 9 French centers. Cabazitaxel was initiated at a dose of 25 mg/m2 q3week. A reduced dose (20 mg/m2 q3w) or an alternative schedule (mainly 16 mg/m2 q2w) was increasingly used for subsequent rechallenges. Progression‐free survival, prostate‐specific antigen (PSA) response, best clinical response, and grade ≥3 toxicities were collected. Overall survival was calculated from various time points. Results Twenty‐two patients with an initial response to cabazitaxel were rechallenged at least twice. The median number of cabazitaxel cycles was 7 at first cabazitaxel treatment, 6 at first rechallenge, and 5 at subsequent rechallenges. Median progression‐free survival at first rechallenge was 9.6 months and 5.6 months at second rechallenge. Median overall survival was 50.9 months from the first cabazitaxel dose, 114.9 months from first life‐extending therapy initiation in mCRPC, and 105 months from mCRPC diagnosis. There was no cumulative grade ≥3 neuropathy or nail disorder and one case of febrile neutropenia. Conclusion Cabazitaxel multiple rechallenges may be a treatment option without cumulative toxicity in heavily pretreated patients having a good response to first cabazitaxel use and still fit to receive it. Novelty & Impact Statements Patients with metastatic castration‐resistant prostate cancer can be treated with Cabazitaxel after docetaxel and androgen receptor‐targeted agent. This chemotherapy can be used multiple times with efficacy and manageable toxicity., We assessed the efficacy and toxicity of multiple rechallenges with cabazitaxel for 22 patients with metastatic castration‐resistant prostate cancer (mCRPC). Median overall survival was 50.9 months from the first cabazitaxel dose, 114.9 months from first life‐extending therapy initiation in mCRPC, and 105 months from mCRPC diagnosis. Cabazitaxel rechallenge may be an effective option in heavily pretreated mCRPC patients with a good initial response to cabazitaxel and still fit to receive it, without cumulative grade ≥3 toxicity.

New anti-cancer therapeutics have been developed in the recent years and dramatically change prognosis and patient management. Either used alone or in combination, immune checkpoint inhibitors (ICI), such as anti-CTLA-4 and anti-PD1/PD-(L)1, act by removing T-cell inhibition to enhance their antitumor response. This change in therapeutic targets leads to a break in immune-tolerance and a unique toxicity profile resulting in immune complications. These side effects, called Immune-Related Adverse Events (IrAEs), can affect all organs, with a wide range of clinical and biological presentations and severity. Various rheumatic and musculoskeletal manifestations have been reported in the literature, ranging from mild arthralgia, polymyalgia rheumatica, to genuine serodefined rheumatoid arthritis and myositis. Tolerance studies suggest some correlations between IrAEs occurrence and tumor response. Assessment of patient musculoskeletal status prior to the start of the ICI is warranted. Management of rheumatic IrAEs does not usually request ICI discontinuation, exception for myositis or very severe forms where it should be discussed. Treatment relies on non-steroidal anti-inflammatory drugs (NSAIDs) or low dose glucocortioids (

Patient-Derived Xenografts (PDXs) in the Chorioallantoic Membrane (CAM) are a representative model for studying human tumors. Circulating Tumor Cells (CTCs) are involved in cancer dissemination and treatment resistance mechanisms. To facilitate research and deep analysis of these few cells, significant efforts were made to expand them. We evaluated here whether the isolation of fresh CTCs from patients with metastatic cancers could provide a reliable tumor model after a CAM xenograft. We enrolled 35 patients, with breast, prostate, or lung metastatic cancers. We performed microfluidic-based CTC enrichment. After 48–72 h of culture, the CTCs were engrafted onto the CAM of embryonated chicken eggs at day 9 of embryonic development (EDD9). The tumors were resected 9 days after engraftment and histopathological, immunochemical, and genomic analyses were performed. We obtained in ovo tumors for 61% of the patients. Dedifferentiated small tumors with spindle-shaped cells were observed. The epithelial-to-mesenchymal transition of CTCs could explain this phenotype. Beyond the feasibility of NGS in this model, we have highlighted a genomic concordance between the in ovo tumor and the original patient’s tumor for constitutional polymorphism and somatic alteration in one patient. Alu DNA sequences were detected in the chicken embryo’s distant organs, supporting the idea of dedifferentiated cells with aggressive behavior. To our knowledge, we performed the first chicken CAM CTC-derived xenografts with NGS analysis and evidence of CTC dissemination in the chicken embryo.

The impact of immune-related adverse events (irAE) on survival outcomes after single-agent immune checkpoint inhibitors (ICIs) remains unclear. We aimed to evaluate the association between irAEs and ICI efficacy in various malignancies.All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective multicentric series. The primary objective was to assess the impact of all type grade ≥II irAEs on progression-free survival (PFS) and overall survival (OS). IrAEs were first considered as a fixed covariate and included in Cox-regression models. In addition, as irAEs are time-related events and can occur at any point during follow-up, we analysed the occurrence of irAEs as a time-varying covariate.In this cohort of 410 patients, the majority of patients (70%) were treated for non-small cell lung cancer. The ICI was an anti-PD(L)1 for 356 patients (82%) and an anti-CTLA4 for 79 patients (18%). In total 126 (29%) of the patients presented at least one grade ≥II irAEs. The first occurrence of a grade ≥II irAE had a positive impact on PFS and OS when considered as a fixed or as a time-varying covariate (hazard ratio [HR] for PFS = 0.63, 95% confidence interval [CI] 0.50-0.81; P = 0.00022; HR for OS = 0.57, 95% CI 0.43-0.74, P 0.0001). This overall finding was confirmed in patients treated with an anti-PD(L)1 and among patients with lung cancer.In this pooled multi-institutional cohort, the incidence of irAEs was associated with better long-term survival across different malignancies treated with ICI monotherapy.

International audience; BACKGROUND: Recent studies suggest improvements in response to salvage chemotherapy (CT) after immune checkpoint inhibitors (ICIs) in several types of cancer. Our objective was to assess the efficacy of chemotherapy re-challenge after ICI, compared with second-line chemotherapy without previous ICI in patients with locally advanced or metastatic urothelial carcinoma (la/mUC). METHODS: In this multicentre retrospective study, we included all patients with la/mUC initiating second or third-line chemotherapy from January 2015 to June 2020. We compared patients treated with second-line chemotherapy without previous ICI (CT2) and patients treated with third-line chemotherapy after ICI (CT3). The primary end-point was objective response rate (ORR) in CT3 compared with CT2. Secondary end-points included progression-free survival (PFS) and toxicities. RESULTS: Overall, 553 patients were included. ORRs were 31.0% (95% CI, 26.5 to 35.5) and 29.2% (95% CI, 21.9 to 36.6), respectively, in CT2 and CT3, with no statistically significant differences (P = 0.62). In subgroup analyses, no differences in ORR were observed by Bellmunt risk group, type of chemotherapy (platinum or taxanes), duration of response to first-platinum-based chemotherapy (< or ≥ 12 months) or FGFR-status. Median PFS was 4.6 months (95% CI, 3.9 to 5.1) and 4.9 months (95% CI, 4.1 to 5.5) in CT2 and CT3, respectively, and grade 3-4 hematologic toxicity occurred in 35.0% and 22.4% of patients. CONCLUSION: This large multicentre retrospective study provides clinically relevant real-world data. Chemotherapy re-challenge after ICI in la/mUC achieves ORR and PFS comparable with those obtained in CT2 with an acceptable safety profile. These updated results offer more promising outcomes than historically reported with second-line chemotherapy data.

International audience; Background: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups.Methods: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment.Findings: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib.Interpretation: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma.

Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are two rare subtypes of kidney cancer with a poor prognosis in the metastatic setting. Beyond first-line treatment, there are no standard-of-care therapies. This retrospective study assessed the efficacy of treatments after first-line chemotherapy in 57 patients with metastatic (m) CDC (n = 35) or RMC (n = 22) treated between 2010 and 2019 at 11 French centers. The median age was 53 years; overall, 60% (n = 34) of patients were metastatic at diagnosis. After a median follow-up of 13 months, the median overall survival was 12 (95% CI, 11–16) months. All patients received first-line platinum chemotherapy ± bevacizumab, with a median time to progression of 7.27 (95% CI, 7–100 months and an objective response rate (ORR) of 39% (95% CI, 26–52%). Patients received a median of two (1–5) treatment lines. Subsequent treatments included tyrosine kinase inhibitors (n = 12), chemotherapy (n = 34), and checkpoint inhibitors (n = 20), with ORR ranging 10–15% and disease control rates ranging 24–50%. The duration of response for all treatments was ~2 months. Notably, nine patients with CDC were still alive > two years after metastatic diagnosis. Beyond first-line therapy, treatments showed very low antitumor activity in mCDC/RMC. A better understanding of the biology of those rare tumors is urgently needed in order to identify potential targets.

Background: In metastatic prostate cancer (PCa) patients, androgen-deprivation therapy (ADT) combined with chemotherapy or next-generation androgen receptor targeted agents is a new standard treatment. The objective of the present study is to assess longitudinal PSA kinetics during treatment using mathematical modeling, to identify the modeled PSA kinetic parameters able to exhibit early prognostic/predictive values. Methods: Phase III clinical trial dataset (NCT00764166) comparing ADT +/− docetaxel in 250 locally treated patients for PCa with rising PSA levels, who were at high risk of metastatic disease was assessed. A kinetic-pharmacodynamic (K-PD) model was used to fit PSA kinetics during the first 100 treatment days, to estimate the modeled PSA production rate K (KPROD) and elimination constant rate K (KELIM). The prognostic value of these parameters, considered as categorized (favorable vs. unfavorable) covariates regarding PSA progression-free survival (PSA-PFS) and overall survival (OS), was assessed using univariate/multivariate analyses. Results: Data from 177/250 patients was assessed. KELIM exhibited a significant prognostic value regarding PSA-PFS and KPROD regarding OS (univariate analysis). In the PSA-PFS final multivariate model, KELIM and the primary therapy type were significant. The OS multivariate model integrated both KPROD and baseline PSA doubling-time. Conclusion: In this first study assessing the modeled PSA kinetics prognostic value in PCa patients treated with systemic treatments, KELIM and KPROD exhibited respective prognostic values regarding PSA-PFS and OS.

International audience; Nivolumab and cabozantinib are approved agents in mRCC patients after sunitinib/pazopanib (TKI) failure. However, the optimal sequence, cabozantinib then nivolumab (CN) or nivolumab then cabozantinib (NC), is still unknown. The CABIR study aimed to identify the optimal sequence between CN and NC after frontline VEGFR-TKI. In this multicenter retrospective study, we collected data from mRCC pts receiving CN or NC, after frontline VEGFR-TKI. A propensity score (PrS) was calculated to manage bias selection, and sequence comparisons were carried out with a cox model on a matched sample 1:1. The primary endpoint was progression-free survival (PFS) from the start of second line to progression in third line (PFS2-3 ). Key secondary endpoints included overall survival from second line (OS2 ). Out of 139 included mRCC patients, 38 (27%) and 101 (73%) received CN and NC, respectively. Overlap in PrS allowed 1:1 matching for each CN pts, with characteristics well balanced. For both PFS2-3 and OS2 , NC sequence was superior to CN (PFS2-3 : HR = 0.58 [0.34-0.98], P = .043; OS2 : 0.66 [0.42-1.05], P = .080). Superior PFS2-3 was in patients treated between 6 and 18 months with prior VEGFR-TKI (P = .019) and was driven by a higher PFSL3 with cabozantinib when given after nivolumab (P

159 Background: Abiraterone acetate (ABI) improves survival in mCRPC. In a previous observational study, worse PSA response and shorter progression-free survival (PFS) were associated with mean ABI plasma through concentration (ABI Cmin) < 8.5 ng/mL within the first three months (ms) of treatment (Carton E et al. Eur J Cancer 2017). The OPTIMABI study, a multicenter non-randomized study (NCT 03458247), aimed to investigate whether a dose escalation of ABI improve PFS in underexposed progressive mCRPC pts. Methods: In step 1, pts with docetaxel-naive progressive mCRPC received ABI at the standard dose of 1000 mg/d + Prednisone 10 mg/d. Mean ABI Cmin was calculated from three monthly dosages. Pts experiencing progression within the first 6 ms and for whom mean ABI Cmin was < 8.5 ng/mL were included in step 2 and received 1000 mg twice daily (2000 mg/d) of ABI. ABI Cmin was assessed every month. The primary endpoint was the non-progression rate at 12 weeks in step 2. Identification of risk factors of 6 ms-PFS was done using Cox regression analysis. Results: From 06/2018 to 09/2021, 81 of 93 pts (median age: 72 yrs) included in step 1 were evaluable for statistical analysis. The median ABI Cmin was 10.0 (IQR: 4.5-15. 0) ng/mL over the first three ms. Inter-individual variability was 59%. The 6 ms-PFS was 68% (IC 95%: 56% - 80%) with no statistical difference between pts with mean ABI Cmin ≥ or < 8.5 ng/mL (log-rank test, p= 0.24). In multivariate analysis, liver metastasis (Hazard ratio, HR = 5.95, CI95% = 1.22–28.92; p=0.027) and creatinine clearance < 60 mL/min (HR = 3.51, CI95% = 1.12–10.99; p=0.031) were independently associated with 6 ms-PFS. Among 21 pts (25.9%), with mean ABI Cmin < 8.5 ng/mL, 8 pts (38.1%) experienced tumor progression within the first 6 ms; four of them could be included in step 2. None of them fulfilled the primary endpoint despite a significant increase in plasma ABI Cmin (p

607 Background: To date, no biomarker of efficacy of nivolumab+/-ipilimumab (N+/-I) or anti-VEGFR TKI has been prospectively validated in mRCC. The BIONIKK trial showed promising objective response rate (ORR) and progression-free survival (PFS) with these treatments in first line (L1) after selection by tumour molecular group. We report OS and efficacy results of the second-line (L2) treatment. Methods: BIONIKK is a French multicentre non-comparative phase II trial, randomising 199 mRCC pts to receive N (58), NI (101) or TKI (40) in L1 according to four molecular groups (ccrcc1-4). ORR and PFS were already reported. With an additional follow-up of ≥20 months, we report OS from randomization and from the start of L2, as well as ORR and PFS with a TKI in L2 by molecular group. Results: With a median follow-up of 42.1 months (40.5-45.2), 86 (43%) patients died: 27/58 (46.5%), 39/101 (39%) and 20/40 (50%) in the N, NI, and TKI arm, respectively. Median OS were 43.4 months (95%CI=31.4-NR) with N, 52.7 months (95%CI=46-NR) with NI and 38.1 months (95%CI=33.2-NR) with TKI (table). 175 (88%) patients discontinued first-line treatment, including 20 deaths, and 129 (74%) received a L2, 38/58 (65.5%), 64/101 (63%), and 27/40 (67.5%) after N, NI and TKI, respectively. The most frequent L2 received after N+/-I was a TKI in 96/102 (94%) pts, including cabozantinib in 49, sunitinib/pazopanib in 32, axitinib in 13, and lenvatinib in 2. N was the most frequent L2 after TKI, 20/27 (74%). ORR with TKI in L2 was 28.5% (10/35) after N, 39% (24/61) after NI and 80% (4/5) after TKI, with marked benefit in ccrcc2 pts (table). The mPFS with TKI in L2 was 8.2 (95%CI=6.9-19.3) after N, 11.4 (95%CI= 8.9-16.8) after NI, and 12.1 (95%CI =11.4-NR) months after TKI, with a higher benefit in ccrcc2 pts (vs. ccrcc1+4, p=0.04). Conversely, ORR and mPFS with N after TKI in ccrcc2-pts were 12.5% (2/16) and 5.4 (2.6-NR) months, respectively. Median OS L2 was reported in the table. The updated ORR and PFS in L1 will presented at the Meeting, as well as PFS2 and efficacy by TKI type in L2. Conclusions: We report for the first-time OS and L2 efficacy results by molecular group in a randomized trial. Molecular selection also has an impact on treatment efficacy in L2. These results, together with those reported in L1, can inform clinicians on the best treatment sequence in L1-2. Clinical trial information: NCT02960906 . [Table: see text]

Polynomial parametric models of ARX structure are becoming increasingly popular for characterizing heat transfer for linear thermal systems with time invariant coefficients. This stems from their robustness when applied to inverse problems, either for model reduction, for experimental model identification or for inverse input problems. Their parsimonious character allows to get residuals of very low levels with a limited number of coefficients. This paper shows, on a theoretical algebraic basis, that ARX models can be deduced from convolutive models.

Renal-cell carcinoma (RCC) accounts for 2% of cancer diagnoses and deaths worldwide. Clear-cell RCCs represent the vast majority (85%) of kidney cancers and are considered morphologically and genetically as immunogenic tumors. Indeed, the RCC tumoral microenvironment comprises T cells and myeloid cells in an immunosuppressive state, providing an opportunity to restore their activity through immunotherapy. Standard first-line systemic treatment for metastatic patients includes immune-checkpoint inhibitors (ICIs) targeting PD1, in combination with either another ICI or with antiangiogenic targeted therapy. During the past few years, several combinations have been approved with an overall survival benefit and overall response rate that depend on the combination. Interestingly, some patients achieve prolonged complete responses, raising the question of whether these metastatic RCC patients can be cured. This review will focus on recent therapeutic advances in RCC and the clinical and biological aspects underpinning the potential for healing.

HER2-dependent signaling may support the development of metastatic castration-resistant prostate cancer (mCRPC) by activating androgen receptor signaling through ligand-independent mechanisms. From 41 mCRPC patients (including 31 treated with Androgen Receptor Signaling Inhibitors [ARSI]), Circulating Tumor Cells (CTCs) were prospectively enriched with AdnaTest platform and analyzed with a multiplexed assay for HER2 and AR-V7 mRNA expression. Then, we evaluated the impact of HER2 expression on PSA-response, Progression Free Survival (PFS) and Overall Survival (OS). HER2 expression was detected in CTCs of 26 patients (63%). Although PSA response was similar regardless of HER2 status, patients with HER2 positive CTCs had shorter PSA-PFS (median: 6.2 months versus 13.0 months, p = 0.034) and radiological-PFS (6.8 months versus 25.6 months, p = 0.022) than patients without HER2 expression. HER2 expression was also associated with a shorter OS (22.7 months versus not reached, p = 0.05). In patients treated with ARSI, multivariate analyses revealed that the prognostic impact of HER2 status on PSA-PFS was independent of AR-V7 expression and of the detection of CTCs by an AdnaTest. We showed for the first time the poor prognostic value of HER2 expression in CTCs from patients with mCRPC. The therapeutic interest of targeting this actionable pathway remains to be explored.

Simple Summary Although the role of HER2 in prostate cancer remains controversial, HER2 can be overexpressed during prostate cancer progression. In this study, we prospectively isolated circulating tumor cells (CTCs) from 41 men with metastatic castration-resistant prostate cancer (mCRPC). Then, we analyzed HER2 expression in CTCs with a highly sensitive assay. HER2 was frequently detected in CTCs of patients (n = 26, 63%) and we showed, for the first time, to our knowledge, that HER2 expression in CTCs was associated with poor long-term clinical outcomes in mCRPC. Moreover, the impact of HER2 expression in CTCs was an independent prognostic factor of progression-free survival. Abstract HER2-dependent signaling may support the development of metastatic castration-resistant prostate cancer (mCRPC) by activating androgen receptor signaling through ligand-independent mechanisms. From 41 mCRPC patients (including 31 treated with Androgen Receptor Signaling Inhibitors [ARSI]), Circulating Tumor Cells (CTCs) were prospectively enriched with AdnaTest platform and analyzed with a multiplexed assay for HER2 and AR-V7 mRNA expression. Then, we evaluated the impact of HER2 expression on PSA-response, Progression Free Survival (PFS) and Overall Survival (OS). HER2 expression was detected in CTCs of 26 patients (63%). Although PSA response was similar regardless of HER2 status, patients with HER2 positive CTCs had shorter PSA-PFS (median: 6.2 months versus 13.0 months, p = 0.034) and radiological-PFS (6.8 months versus 25.6 months, p = 0.022) than patients without HER2 expression. HER2 expression was also associated with a shorter OS (22.7 months versus not reached, p = 0.05). In patients treated with ARSI, multivariate analyses revealed that the prognostic impact of HER2 status on PSA-PFS was independent of AR-V7 expression and of the detection of CTCs by an AdnaTest. We showed for the first time the poor prognostic value of HER2 expression in CTCs from patients with mCRPC. The therapeutic interest of targeting this actionable pathway remains to be explored.

The immune checkpoint inhibitors (CPI) such as anti-PD(L)1 or anti-CTLA4 had improved long-term patients' outcomes in different malignancies. Thyroid disorders are the most frequent endocrine side effects from CPI reported in clinical trials and in clinical routine practice. The incidence of thyroid dysfunction is variable according to ICP used (more frequent under anti-programmed cell death 1 (PD1) or anti-programmed cell death-ligand 1 (PDL1)). Most thyroid dysfunctions have been reported to occur 2 to 4 courses after CPI initiation. The clinical symptoms are generally nonspecific (asthenia, weight change, rarely cardiac rhythm disorder). These thyroid dysfunctions are commonly painless thyroiditis with a biphasic evolution: thyrotoxicosis followed by a secondary hypothyroidism frequently definitive. Diagnosis is made on a thyroid test (TSH and FT4). In most cases, no further exam is necessary. Beta blockers therapy is recommended in symptomatic thyrotoxicosis with palpitations. Thyroid hormones therapy will be introduced quickly in case of hypothyroidism. Thyroid dysfunctions are not a contra-indication to the continuation of immunotherapy. Due to the high frequency of these complications, close monitoring of the thyroid status is recommended under CPI.

Platinum-based chemotherapy is commonly associated with toxic sensory neuropathies, but also, although rarely, with Guillain-Barré syndrome (GBS). We describe five patients who developed GBS while receiving platinum-based chemotherapy for a solid tumor and report the five cases published so far. Most patients had received cumulative platinum doses below known neurotoxic levels, and all of them had an optimal outcome after platinum discontinuation, associated in most cases with administration of intravenous immunoglobulin. Clinical presentation, electroneuromyography, and cerebrospinal fluid analysis help clinicians to differentiate GBS from toxic neuropathy. Platinum compounds are the only chemotherapeutic agents used for solid tumors that have been associated to GBS. Thus, we propose that GBS may constitute a non–dose-dependent side effect of platinum drugs and that awareness needs to be raised among oncologists on this rare but potentially life-threatening complication of platinum chemotherapy. Implications for Practice: Many patients on platinum-based chemotherapy for solid tumors develop sensory neuropathy, a common dose-dependent side effect. The authors propose that Guillain-Barré syndrome may constitute an immune-mediated, non-dose-related side effect of platinum-based chemotherapy. Prompt diagnosis of Guillain-Barré syndrome and distinction from classical toxic neuropathy are crucial for optimal treatment. Platinum discontinuation, associated if needed to intravenous immunoglobulin administration, radically changes the course of the disease and minimizes neurological sequelae.

Models using Cattaneo and Vernotte hyperbolic heat equation or derived from it (Double Phase Lag model and their various versions) are very common in the present thermal literature, especially for simulating heat transfer at the meso scale, such as in bio heat transfer. Such papers refer to so-called experimental validations made in several previous articles. We show in this short review that the corresponding experiments were biased, because of a deficient methodological approach based on too simple assumptions or on poor data reduction techniques.

In this chapter, a theoretical study relying on the thermal modelling of a Curie wheel, used for the conversion of low-grade waste heat into electrical power, is presented. It allows understanding the thermal behaviour of a Curie wheel operating in steady state in order to optimise its design. To this end, a stationary one-dimensional analytical thermal model, based on a Lagrangian approach, was developed. It allows determining the local distribution over time of the temperature in the magnetocaloric material exposed to a periodic sinusoidal heat source. Thanks to this model, the effects of different parameters (nature of the magnetocaloric material, nature and temperature of the fluid) were determined and analysed.

5019 Background: The Phase III PROpel (NCT03732820) trial demonstrated at interim analysis a statistically significant clinical benefit from combining ola + abi in the first-line (1L) mCRPC setting vs placebo (pbo) + abi. Benefit was seen irrespective of a pt’s homologous recombination repair mutation (HRRm) status; median radiographic progression-free survival (rPFS) 24.8 for ola + abi vs 16.6 months for pbo + abi (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P

[Background] There are limited data on toxicity and surgical safety associated with neoadjuvant programmed death ligand 1 (PD-L1) inhibitors prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC)., [Objective] To present a comprehensive safety analysis of the largest neoadjuvant series, with focus on timing and severity of toxicity and surgical complications occurring after neoadjuvant atezolizumab in patients with MIBC enrolled in the ABACUS trial., [Design, setting, and participants] ABACUS (NCT02662309) is an open-label, multicenter, phase II trial for patients with histologically confirmed (T2-T4aN0M0) MIBC, awaiting RC. Patients either were ineligible or refused cisplatin-based neoadjuvant chemotherapy., [Intervention] Two cycles of neoadjuvant atezolizumab (1200 mg, every 3 wk) followed by RC., [Outcome measurements and statistical analysis] Description of atezolizumab toxicity profile in the neoadjuvant setting, impact on surgery, and delayed immune-mediated adverse events (AEs) were assessed., [Results and limitations] Ninety-five patients received treatment. Of them, 44% (42/95) had atezolizumab-related AEs during the neoadjuvant period (fatigue [20%], decreased appetite [6%], and transaminases increased [6%]). Treatment-related grade 3–5 AEs occurred in 11% (10/95) of patients during the study. Of the patients, 21% (20/95) received only one cycle of atezolizumab due to AEs; 92% (87/95) underwent RC. No surgery was delayed due to atezolizumab-related toxicities. Surgical complications occurred in 62% (54/87) of patients. Of these patients, 43% (37/87) and 20% (17/87) had minor (grade 1–2) and major (grade 3–5) complications, respectively. Thirteen of 87 (15%) patients had post-RC atezolizumab-related AEs, including adrenal insufficiency and transaminases increased. Three deaths occurred during the period of study-related interventions (one non–treatment-related aspiration pneumonia, one immune-related myocardial infarction, and one cardiogenic shock after RC). Not all surgical safety parameters were available., [Conclusions] Two cycles of neoadjuvant atezolizumab are well tolerated and do not seem to impact surgical complication rates. Owing to the long half-life, AEs may occur in the postoperative period, including endocrine abnormalities requiring attention and intervention., [Patient summary] Here, we report a comprehensive dataset of patients receiving neoadjuvant immune checkpoint inhibitors before radical cystectomy. Treatment with neoadjuvant atezolizumab is safe and does not seem to complicate surgery significantly., Queen Mary University of London was the Sponsor of the study. Roche granted QMUL funding for the study. J. Bull and M. Jacobson also provided financial support for aspects of the biomarker analysis. We acknowledge Cancer Research UK, the UK Experimental Cancer Medicine Network, and La Roche-Hoffmann for funding.

Acute Kidney Injury (AKI), induced by Checkpoint Inhibitors therapies (CPI-induced AKI), is an uncommon but severe Immune-Related Adverse Event (IRAE). The aim was to describe the epidemiology, risks factors, clinical, and laboratory characteristics of these renal adverse events (AEs) in a real-life cohort treatment.Consecutive patients undergoing a checkpoint inhibitor (CPI) therapy at the Hôpital Lyon Sud from January 2015 to July 2017 were included. A systematic retrospective analysis of medical files was performed, monthly serum creatinine levels, associated treatments, and occurrence of other IRAEs data were collected. AKI episodes explained by classic AKI aetiologies (prerenal, obstructive, septic) were excluded from the analysis.CPI-induced AKI incidence was 3.7% (13/352) and appeared to be time-dependent (7.7% (11/143) for patients with3 months of CPI exposure), ranging from 1 to 16 months. All cases with available histology were acute tubulointerstitial nephritis (ATIN), with poor urinary sediment. The severity of AKI was mild (stage 1 in 50% of cases), with no need for renal-replacement therapy. Although CPI-induced AKI patients had more frequently other IRAEs (77% versus 39%), this was not associated with a greater risk of AKI. Pre-existing chronic kidney disease (defined as an estimated glomerular filtration rate (eGFR)60 ml/min) was not associated with a greater risk of CPI-induced AKI. Treatments of CPI-induced AKI were heterogeneous, with discontinuation of CPIs, and inconstant systemic corticosteroid therapy.The monitoring of renal function and early identification of AKI during CPIs treatment is essential. The optimal management of CPI-induced AKI remains unclear and requires a close collaboration between the oncology and nephrology departments.Immune checkpoint inhibitors (CPIs) have dramatically improved patient outcomes in different malignant contexts such as melanoma, non-small cell lung cancers (NSCLC) and urologic cancers. Usually well-tolerated, CPIs are however associated with immune-related adverse events (IRAEs). Among them, acute kidney injury (AKI) is uncommon, and not well-described. Following the exponential increase in the prescription of CPIs, previously uncommon cases of IRAEs (such as AKI) have become common occurrence in referral centres. Data regarding the epidemiology, risk factors, or management of CPI-induced AKI are currently lacking or can be discordant. Data regarding CPI-induced AKI, in a large real-life cohort were reported herein.

The advent of immune checkpoint-inhibitors (CPI) has transformed treatment for several cancer types. This review was performed to assess the rate of adverse events (AEs) associated with the use of CPI, alone or in combinations. A review of AEs reporting quality was also performed. All publications of Randomized Clinical Trials (RCTs) assessing CPI published before December 2017 were included. To investigate the quality of AEs reporting, a set of items was defined based on the 2004 CONSORT harms extension statement. Rates of Grade 5, serious, and study-withdrawal related AEs were collected in each treatment category. Specific immune related AEs (irAEs) were also collected when available. Pooled estimates of adverse event rates were calculated by using generalized linear mixed model. A total of 35 RCTs including 16,485 patients were included. The overall quality of AEs reporting was satisfactory, but items pertaining to methods of data collection and analysis were infrequently reported. Grade ≥ 3 AEs were reported for 14% (95% CI 12-16) of patients treated with PD(L)-1 inhibitors, 34% (95% CI 27-42) of patients treated with CTLA-4 inhibitors, 55% (95% CI 51-59) of patients on CPI combinations and 46% (95% CI 40-53) of patients on immunotherapy-chemotherapy combination. The profile of irAEs was different among the treatment categories. The use of CPI, especially in combination, is associated with significant rates of Grade ≥ 3 AEs. Healthcare planning should anticipate the expected high number of patients presenting with irAEs in the future.

An Inverse Heat Conduction Problem (IHCP) is considered in order to estimate the transient heat flux extracted from a hot solid surface by an impinging droplet. The resolution of the IHCP is made with the so-called quadrupole method, which provides an analytical expression of the temperature and the heat flux at the front surface of the solid wall, where the drop impact takes place. In the experiments, the thermal response of the front surface is recorded using IR thermography. For that, sapphire is chosen as the material of the solid wall, and the front surface is coated with a thin TiAlN ceramic layer (thickness of 300 nm). The latter is highly emissive and opaque in the IR while sapphire is transparent at the same wavelengths. This feature allows the surface impacted by the droplet to be viewed from the bottom by the IR camera. This approach has been implemented to gain some insights into the heat transfer from the solid surface as well as the formation and growth of the vapor film, which appears under the droplet in the regime of film boiling, when the solid temperature is much higher than the boiling temperature of the liquid. Due to the small thickness of the vapor film, heat conduction is predominant in the vapor layer. Hence, the thickness of the vapor film can be deduced from the value of the reconstructed local heat flux, assuming a linear profile of temperature between the liquid interface of the droplet at the saturation temperature and the solid surface measured by IR thermometry.

Immunotherapy (IO) with checkpoint inhibitors with or without anti-angiogenic tyrosine kinase inhibitor (TKI)-based combinations have demonstrated superior efficacy over sunitinib for treatment-naive patients with metastatic clear-cell renal cell carcinoma (mRCC). Four of these combinations (nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib and pembrolizumab plus lenvatinib) represent new front-line standard-of-care options for mRCC patients, according to the International Metastatic RCC Database Consortium (IMDC) subgroups. Questions over the optimal treatment between IO-IO or IO-TKI combinations for mRCC patients in intermediate/poor IMDC risk groups and the optimal IO-TKI regimen for all IMDC risk groups remain unanswered. This review will focus on the biological pathways that have driven the hypothesis of a synergistic combination of such agents and their efficacy results, with consideration of response and survival outcomes in the overall population of phase three pivotal trials as well as in specific subgroups of interest.

International audience; The transient profiles of temperature and normal heat flux inside a flat mi-nichannel heated by a surface heat source are constructed from temperature measurement over its external heated face. It uses analytical expressions of the corresponding transfer functions which are calculated using Laplace and Fourier integral transforms. Firstly, this estimation technique is verified on synthetic outputs of a finite elements code (COMSOL). Then it is implemented on an experimental minifluidic bench with electrical heating and temperature measurement by thermocouples and infrared thermography, for a low Péclet number of the flow. The presented results show that the heat source can be recovered at any time, as well as the internal normal heat flux and temperature distributions, including the bulk temperature of the liquid flow.; Les profils transitoires de température et de composante normale de la densité de flux à l'intérieur d'un mini-canal plan chauffé par une source surfacique de chaleur sont reconstitués à partir de mesures de température sur sa surface externe excitée. Le modèle qu'on inverse utilise des expressions analytiques des fonctions de transfert correspondantes qui sont calculées en utilisant les transformations intégrales de Laplace et de Fourier. Cette technique d'estimation est tout d'abord testée sur des sorties synthétiques d'un code aux éléments finis (COMSOL). Puis elle est mise en oeuvre sur un banc expérimental en mini-fluidique avec chauffage électrique et mesures de température par thermocouples et thermographie infrarouge, pour des nombres de Péclet faibles de l'écoulement. Les résultats présentés montrent qu'on peut reconstituer la source de chaleur à tout instant, ainsi que les distributions de tempéralure et de densité normale de flux, ainsi que de température moyenne de mélange de l'écoulement..

The majority of patients with prostate cancer who later develop lethal metastatic disease have high-risk localized disease at presentation, emphasizing the importance of effective treatment strategies at this stage. Multimodal treatment approaches that combine systemic and local therapies offer a promising strategy for improving the clinical outcomes of patients with high-risk localized prostate cancer. Combinations of neoadjuvant and adjuvant chemotherapy, hormonal therapy, or chemohormonal therapy are considered to be the standard of care in most solid tumours and should be investigated in the future for the treatment of prostate cancer to improve patient outcomes. However, although the combination of androgen deprivation therapy and radiotherapy is a standard of care in high-risk localized or locally advanced prostate cancer, the benefit of chemotherapy or chemohormonal therapy has yet to be demonstrated outside of the metastatic setting. Moreover, the benefit of neoadjuvant and/or adjuvant systemic therapies in combination with radical prostatectomy has not been proved. The development of next-generation hormonal agents, which have been approved for the treatment of castration-resistant prostate cancer, offers further therapeutic possibilities that are being assessed in early-phase clinical trials.

A Carnot-type engine with a changing phase working fluid is modelled and optimized. The engine is externally heated by a waste heat in order to valorize it. The waste heat is a flue gas at 350 °C, corresponding to a usual temperature of industrial furnace effluents. The objective function is the maximization of the net power output. In the numerical application, the working fluid is water. The optimization variables are the working fluid temperature of vaporization, its temperature of condensation and the allocation of a total thermal transfer area between the boiler and the condenser. This article aims to define an upper bound for waste heat to power conversion, depending on the waste heat temperature and its available mass flow rate, on the working fluid used and on the exchangers’ size. The methodology used can be applied to optimize other externally heated engines. Different control volumes are selected for the analysis: the adiabatic converter, the non-adiabatic converter, the system (the converter and the exchangers) and the system placed in the environment. The impact of the choice of the control volume on optimization results, global efficiency and entropy production is studied. It appears that the optimal heating and cooling temperatures are the same in all sub-systems, but the optimal allocation of the total thermal transfer area differs slightly. However, in all cases the optimal condenser thermal transfer area is larger than the optimal boiler thermal transfer area. This imbalance corresponds to the need to evacuate the mechanical energy degradation into heat. It also appears that the control volume increase implies a decrease of the first law efficiency. The entropy analysis allows an identification and a quantification of the different contributions to entropy production. Then, a sensitivity analysis to the relevant parameters is carried out. The relevant parameters are the heating fluid temperature and mass flow rate, the total thermal transfer area, the compressor efficiency and the turbine efficiency.

492 Background: Immune checkpoints inhibitors (ICIs) have recently changed therapeutic landscape of la/mUC. Recent studies suggested an improvement of response to salvage chemotherapy (CT) after ICIs in several cancer types including urothelial carcinoma. We assumed that efficacy of CT rechallenge after ICIs may be improved compared to second-line CT without previous ICIs in patients (pts) with la/mUC. Methods: CIMUC is a French multicentric retrospective study including all pts with la/mUC initiating second or third-line CT from January 1st 2015 to June 30th 2020. Two groups of pts were defined: pts in group 1 (G1) were treated with a second-line CT without previous ICIs; pts in group 2 (G2) were treated with third line CT after ICIs. Primary endpoint was objective response rate (ORR: proportion of patients with complete or partial response, according to RECIST 1.1 criteria) in G2 versus G1. Secondary endpoints were progression-free survival (PFS), defined as time from initiation of second or third-line CT to disease progression or death from any cause, and toxicities. This study is supported by the French Genito Urinary Group (GETUG). Results: 553 pts were included. Baseline characteristics of the 2 groups are summarized in the Table. ORRs were 31% (95%CI [26.5-35.5]) and 29.2% (95%CI [21.9-36.6]) respectively in G1 and G2, without statistically significant difference (p=0.617), even after adjustment for Bellmunt risk factors (p=0.3214). In subgroups analysis, no difference in ORR was observed by type of CT (platinum or taxanes), duration of response (DOR) to first-platinum-based CT (< 12 months or ≥ 12 months) and FGFR-status. We did not identify any predictive factor of OR in G2 in multivariate analysis. Median PFS were 4.6 months (95%CI [3.88; 5.06]) and 4.86 months (95%CI [4.11; 5.45]), respectively in G1 and G2. Grade 3/4 hematologic toxicity occurred in 35% and 22.4%, respectively in G1 and G2. Conclusions: While ORR was not superior in G2 versus G1, pts derive comparable benefit in a further line of treatment (G2) in terms of ORR and PFS. Despite limits inherent to any retrospective study, CIMUC represents one of the largest retrospective studies in this setting.[Table: see text]

A thermohydraulic analytical model of a capillary cylindrical heat pipe in steady-state is proposed in this article. It is based on an original representation by thermal quadrupoles to describe heat transfer in the wall and in the porous wick, via the use of Fourier integral transforms. Thanks to a validation from literature results, this model provides two-dimensional axisymetric thermal fields and one-dimensional pressure and velocity profiles of both liquid and vapour flows. Different developments and solutions are introduced according to the kind of boundary conditions at evaporator and at condenser, and with a more or less strong thermohydraulic coupling at the liquid/vapour interface. For the simple case with imposed uniform heat fluxes, intrinsic properties of the heat pipe are originally defined. The introduced model offers a generalisation of analytical models of standard heat pipe as a design or optimisation tool. Wider developments of analytical models for more complex three-dimensional geometries of heat pipe and in transient regime can be expected.

Parametric models of ARX structure express the relationship between an input u ( t ) and one output y a r x ( t ) . The purpose of the study is first to identify such a transient model through temperature measurements in a calibration experiment. It relates the output, that is the temperature response at the outlet of each of the two fluids that flow inside the heat exchanger, to the temperature increase at the inlet of the hot fluid, considered as a transient thermal input. This model is validated in a different experiment and transient perturbation experiments are run with maldistribution or flowrate changes. They are processed in order to detect such structural changes with respect to the calibrated model and to get the steady state characteristics, transmittances and effectivenesses, of the exchanger. The advantages and drawbacks of this non-destructive technique, which does not rely on any heat transfer correlation, are detailed and discussed.

Emerging evidence from population-based and retrospective series suggests a potential improvement of clinical outcomes in metastatic prostate cancer. Moreover, metastasis-directed treatment has shown encouraging results in this setting. There is an increasing interest in exploring the potential of local therapies in advanced prostate cancer, but this has rarely been specifically addressed in the castration-resistant state, whether non-metastatic or metastatic. A review of relevant articles was performed on the oncologic benefit of local treatment of the primary tumor or metastasis-targeted treatment in castration-resistant prostate cancer patients. The main goal of this strategy is to delay introduction of a new systemic agent to maintain quality of life and potentially to limit resistance. Further investigation is required to provide high-level evidence for the oncologic benefit of this treatment modality.

Vacuum holding induction furnaces are used for the manufacturing of turbine blades by loss wax foundry process. The control of solidification parameters is a key factor for the manufacturing of these parts. The definition of the structure of a reduced heat transfer model with experimental identification through an estimation of its parameters is required here. Internal sensors outputs, together with this model, can be used for assessing the thermal state of the furnace through an inverse approach, for a better control. Here, an axisymmetric furnace and its load have been numerically modelled using FlexPDE, a finite elements code. The internal induction heat source as well as the transient radiative transfer inside the furnace are calculated through this detailed model. A reduced lumped body model has been constructed to represent the numerical furnace. The model reduction and the estimation of the parameters of the lumped body have been made using a Levenberg-Marquardt least squares minimization algorithm, using two synthetic temperature signals with a further validation test.

International audience; This article presents a method for estimating the time dependent generation rate of an aerosol source starting from a transient concentration signal measured at a distant point. The method is made up of two distinct steps: a calibration phase, followed by an estimation phase. The calibration phase consists in identifying a transfer function (termed "impedance") between a known source (the " calibration source ") and its measured concentration response. In the second step the unknown source generation rate, in the configuration of interest, is estimated by inversion of the corresponding measured concentration signal at the same point, using the previously identified impedance. The time integral of this generation rate, the emitted aerosol dose, can be calculated directly, starting from the integral of the (transient) impedance. Here both simulation of inversions and application to a real experiment have been implemented. The results confirm that it is possible to estimate the temporal pattern of injection and the global emitted mass of pollutant.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.